Program Director/Principal Investigator (Last, First, Middle): SinkO, Patrick J. PROJECT SUMMARY (See instmctlons): The long-term objective of this MERIT renewal remains to design, synthesize, characterize and evaluate novel polymeric drug nanocarriers that enhance anti-AIDS drug bioefficacy by improving delivery, pharmacokinetics, and pharmacodynamics. Our strategy utilizes polymeric bioconjugate-type nanocarriers comprising a novel peptide-polymer scaffold with component agents that: (a) target HIV-infected cells through specific cell-surface receptors, (b) control cellular and body disposition & retention, (c) alter cell uptake pathways, and (d) selectively release drug inside cells. Specific aims: (1) To evaluate nanocarriers for macrophage targeting and anti-HIV activity using multiplex affinity ligands for the formyl peptide receptor, mannose receptor, CCR5 and CXCR4 using protease inhibitors in cells chronically infected with HIV-1; (2) To determine the effect of peptide-polymer scaffold topology, effectors and physical form on cell/organ retention and pharmacokinetics of nanocarriers (polymer-bioconjugate and nanoparticle-types) in major sites of HIV infection; (3) To assess HIV-entry inhibition using nanocarriers with single and /or dual-receptor multiplex ligand binding; (4) To identify transferrin receptor (brain) and CD4 receptor (T-cell, macrophage) binding peptides using a state ofthe art T7 random peptide phage display library and an endocytosis-based selection screening method and evaluate binding in vitro. In addition to delivering a drug payload, a significant advantage of designing nanocarrier bioconjugates that bind to target cell surface receptors is that it is possible to block HIV entry into cells offering a second pathway for reducing/eradicating HIV infection. The proposed MERIT renewal focuses on continuing mechanistic active targeting approaches utilizing novel nanocarriers and peptidic targeting ligands as well as translationai studies that will enable the clinical development of these promising therapeutics. The multiplicity of activities resulting from drug delivery and targeting approaches complements pharmacological approaches and should result in improved potency, bioefficacy and patient outcomes. RELEVANCE (See Instructions): The relatively poor potency of existing anti-AIDS drugs requires that frequent and high doses be administered. Utilizing a nanotechnology approach, the proposed research will develop novel anti-HIV therapeutics that will dramatically increase potency resulting in reduced doses, less frequent administration, reduced side effects, higher patient compliance rates and better therapeutic outcomes.